Patent EA-002333-B1 (EA)
Title: PROCESS FOR PRODUCING 16-SUBSTITUTED 4 AZA-5 alpha -ANDROST-1-EN-3-ONES AND INTERMEDIATES OBTAINED THEREIN
Inventor: HUMPHREY GUY R
IPC: C07D473/00
Filed: 1998-12-18
Abstract: 1. A process for producing a compound of structural formula (11):   wherein: Ar is an unsubstituted or mono- or di-substituted phenyl, naphthyl, or 5-, 6- or 7- membered heteroaromatic ring containing at least one member selected from the group consisting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms, or combinations thereof; in which the heteroaromatic ring can also be fused with one benzo or heteroaromatic ring; produced by: treating a compound of structural formula (10):   with potassium tert-butoxide, and isolating the resulting product (11). 2. The process of Claim 1 additionally comprising the step of producing a compound of structural formula (10):   by treating a compound of structural formula (9):   with trimethylsilylchloride in the presence of an organic base and adding iodine, and isolating the resulting product (10). 3. The process of Claim 2 additionally comprising the step of producing a compound of structural formula (9):   by treating a compound of structural formula (8):   with potassium tert-butoxide and adding Ar-F, and isolating the resulting product (9). 4. The process of Claim 3 additionally comprising the step of producing a compound of structural formula (8):   by hydrogenating a compound of structural formula (7):   and isolating the resulting product (8). 5. The process of Claim 4 additionally comprising the step of producing a compound of structural formula (7):   by treating a compound of structural formula (6):   with lithium tri-sec-butylborohydride, followed by an oxidative workup, and isolating the resulting product (7). 6. The process according to Claim 5, additionally comprising the step of producing a compound of structural formula (6):   by treating a compound of structural formula (5):   with ammonium acetate in boiling acetic acid with backflow condenser, and isolating the resulting product (6). 7. The process according to Claim 6, additionally comprising the step of producing a compound of structural formula (5)   by treating a compound of structural formula (4):   with sodium periodate and catalytic potassium permanganate and sodium carbonate, and isolating the resulting product (5). 8. The process according to Claim 7, additionally comprising the step of producing a compound of structural formula (4):   by treating a compound of structural formula (3):   with 10% Pd/C, cyclohexene, and ethanol in an organic solvent, and isolating the resulting product (4). 9. The process according to Claim 8, additionally comprising the step of producing a compound of structural formula (3):   by treating a compound of structural formula (2):   with aluminum isopropoxide and 2-butanone in the presence of organic base in an organic solvent, followed by addition of aqueous acid to the solution, neutralization with aqueous base and isolation of (3) as a solution in the organic solvent. 10. The process according to Claim 9, additionally comprising the step of producing a compound of structural formula (2):   by treating a compound of structural formula (1):   with methyl magnesium chloride in the presence of cerium chloride in an organic solvent. 11. The process according to Claim 1 wherein Ar is selected from: unsubstituted or mono- or di-substituted phenyl, naphthyl, pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, and benzoxazolyl. 12. The process according to Claim 11 additionally comprising the step of producing a compound of structural formula (10):   by treating a compound of structural formula (9):   with trimethylsilyl chloride in the presence of an organic base and adding iodine, and isolating the resulting product (10). 13. The process according to Claim 12 additionally comprising the step of producing a compound of structural formula (9)   by treating a compound of structural formula (8):   with potassium tert-butoxide and adding Ar-F, and isolating the resulting product (9). 14. A process for producing a compound of structural formula (11):   wherein: Ar is an unsubstituted or mono- or di-substituted phenyl, naphthyl, or 5-, 6- or 7- membered heteroaromatic ring containing at least one atom selected from the group consisting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms, or combinations thereof; in which the heteroaromatic ring can also be fused with one benzo or heteroaromatic ring; comprising: (a) by treating a compound of structural formula (1):   with methyl magnesium chloride in the presence of cerium chloride in an organic solvent to produce (2):   (b) treating the compound of structural formula (2) with aluminum isopropoxide and 2-butanone in the presence of organic base in an organic solvent, followed by addition of aqueous acid to the solution, neutralization with aqueous base and isolation (3) as a solution in the organic solvent:   (c) treating the compound of structural formula (3) with 10% Pd/C, cyclohexene, and ethanol in an organic solvent, and isolating the resulting product (4):   (d) treating the compound of structural formula (4) with sodium periodate and catalytic potassium permanganate and sodium carbonate, and isolating the resulting product (5):   (e) treating the compound of structural formula (5) with ammonium acetate in boiling acetic acid with backflow condenser, and isolating the resulting product (6):    (f) treating the compound of structural formula (6) with lithium tri-sec-butylborohydride, followed by an oxidative workup, and isolating the resulting product (7):   (g) hydrogenating the compound of structural formula (7) and isolating the resulting product (8):   (h) treating the compound of structural formula (8) with potassium tert-butoxide, adding Ar-F, and isolating the resulting product (9):   (i) treating the compound of structural formula (9) with trimethylsilyl chloride in the presence of an organic base and adding iodine, and isolating the resulting product (10):   (i) treating the compound of structural formula (10) with potassium tert-butoxide, and isolating the resulting product (11). 15. The process of Claim 14 wherein Ar is 4-methylphenyl. 16. A compound of structural formula (11):   wherein R<1> is hydrogen atom and R<2> is selected from hydroxy or O-Ar, or R<1> and R<2>, taken together, form oxo group, "a" is a single bond and H is present, or "a" is a double bond and then H is absent, X is hydrogen or iodine. 17. A compound of Claim 16, represented by the formula   18. A compound of Claim 16, represented by the formula   19. A compound of Claim 16, represented by the formula   20. A compound of Claim 16, represented by the formula   21. A compound of general formula   22. A compound of general formula   23. A compound of general formula   24. A compound of general formula